The present invention relates to sulfonic acid ester derivatives, method for the production thereof and use thereof.
As lenitive medicines developed recently, an enkephalinase inhibitor is known. This inhibitor contains a structure derived from 2-aralkyl-3-thiopropionic acid. The stereo-specificity of the 2-position of this structure is known to influence the expression of pharmaceutical action. For example, it is described in European Laid-Open Patent Publication EP-A-0,318,377 that, although both S-form and R-form of N-[2-(acetylthiomethyl)-1-oxo-3-phenyl-propyl] glycine benzyl ester have similar enkephalinase inhibition activities, the S-form has an inhibiting activity against an angiotensin converting enzyme which converts angiotensin I to angiotensin II and has an antihypertensive effect, while, the R-form can be used for therapy of intestinal function disease or intestinal hypersensitive syndrome.
As a method for preparing an optical active 2-aralkyl-3-acetylthiopropionic acid, Japanese Laid-Open Patent Publication No.8-59606 discloses optical resolution using ephedrine. However, the method for preparing an optical active 2-aralkyl-3-acetylthiopropionic acid directly by optical resolution is not economical, because agents for optical resolution are very expensive and the yield of the optical resolution is very low. On the other hand, an optical active 2-aralkyl-3-chloropropionic acid is considered as a precursor for optical active 2-aralkyl-3-thiopropionic acid. In Japanese Laid-Open Patent Publication No.7-316094, it is described that (S)-2-aralkyl-3-chloropropionic acid can be obtained by asymmetrically hydrogenating (S)-2-aralkylidene-3-chloropropionic acid using a complex of ruthenium and an optical active bidentate phosphine as a catalyst in the presence of a tertiary amine. However, this method does not appear to be economical because the catalyst is expensive and hydrogen pressure should be kept high in the reaction system. Furthermore, an optical purity of (S)-2-aralkyl-3-chloropropionic acid obtained by this method is unsatisfactory. It is described in Chemische. Berichte. vol.123, p635-638 (1990) that (R)-2-aralkyl-3-chloropropionic acid can be produced from L-phenylalanine by using 7-step process, including a step of a transfer reaction with a high temperature and a step of enzyme reaction by use of swine liver lipase. However, this method includes many steps of reaction and the transfer reaction with a high temperature which is difficult to practice industrially.
On the other hand, 2-aralkyl-3-sulfonyloxypropionic acid, which is a sulfonic acid ester derivative, is considered to be one of precursors of 2-aralkyl-3-thiopropionic acid. However, synthesis or isolation of racemic compounds or optical active compounds of 2-aralkyl-3-sulfonyloxypropionic acid has not been reported. Therefore, the above mentioned 2-aralkyl-3-sulfonyloxypropionic acid seems to be a novel compound and an industrially applicable producing method has not been established yet.
As stated above, although production methods of an optical active 2-aralkyl-3-thiopropionic acid that is an intermediate of the enkephalinase inhibitor are known, these methods do not seem to be industrially practical in that very expensive reagents are necessary, that industrially unpractical reaction conditions are included, and that optical purity of the product by these methods is low.
The present invention is to provide a novel sulfonic acid ester derivative, 2-aralkyl-3-sulfonyloxypropionic acid having the following general formula (3): 
wherein Ar is an aryl group that may be substituted and R1 is an alkyl group that may be substituted or an aryl group that may be substituted, an industrially advantageous producing method thereof and a method for producing 2-aralkyl-3-thiopropionic acid using the same.
In light of the above situation, after an extensive and intensive series of studies, the present inventors have found out that a novel optical active 2-aralkyl-3-sulfonyloxypropionic acid and a novel optical active 2-aralkyl-3-thiopropionic acid can be produced with high yield by using an optical active 2-aralkyl-3-acyloxy-1-propanol as a starting material and a using novel optical active 2-aralkyl-3-sulfonyloxy-1-propanol as an intermediate.
The present invention relates, in a first aspect, to an optical active 2-aralkyl-3-sulfonyloxy-1-propanol having the following general formula (1): 
wherein Ar is an aryl group that may be substituted, and R1 is methyl group, ethyl group, n-propyl group, isopropyl group, benzyl group, p-chlorophenyl group, p-bromophenyl group, p-methoxyphenyl group, o-nitrophenyl group, m-nitrophenyl group, p-nitrophenyl group or 1-naphthyl group.
The present invention relates, in a second aspect, to a method for producing an optical active 2-aralkyl-3-sulfonyloxy-1-propanol having the following general formula (1): 
wherein Ar is an aryl group that may be substituted and R1 is methyl group, ethyl group, n-propyl group, isopropyl group, benzyl group, p-chlorophenyl group, p-bromophenyl group, p-methoxyphenyl group, o-nitrophenyl group, m-nitrophenyl group, p-nitrophenyl group or 1-naphthyl group, which comprises hydrolyzing, in the presence of a base, an optical active 2-aralkyl-1-acyloxy-3-sulfonyloxypropane having the following general formula (2): 
wherein Ar is an aryl group that may be substituted, R1 is a methyl group, ethyl group, n-propyl group, isopropyl group, benzyl group, p-chlorophenyl group, p-bromophenyl group, p-methoxyphenyl group, o-nitrophenyl group, m-nitrophenyl group, p-nitrophenyl group or 1-naphthyl group and R2 is a linear or branched alkyl group that may be substituted, a linear or branched alkenyl group that may be substituted or an aryl group that may be substituted.
The present invention relates, in a third aspect, to an optical active 2-aralkyl-3-sulfonyloxypropionic acid having the following general formula (3): 
wherein Ar is an aryl group that may be substituted and R1 is an alkyl group that may be substituted or an aryl group that may be substituted.
The present invention relates, in a fourth aspect, to a method for producing an optical active 2-aralkyl-3-sulfonyloxy-propionic acid having the following general formula (3): 
wherein Ar is an aryl group that may be substituted and R1 is an alkyl group that may be substituted or an aryl group that may be substituted, which comprises oxidizing an optical active 2-aralkyl-3-sulfonyloxy-1-propanol having the following general formula (1): 
wherein Ar is an aryl group that may be substituted and R1 is an alkyl group that may be substituted or an aryl group that may be substituted.
The present invention relates, in a fifth aspect, to a method for producing an optical active 2-aralkyl-3-sulfonyloxypropionic acid having the following general formula (3): 
wherein Ar is an aryl group that may be substituted and R1 is an alkyl group that may be substituted or an aryl group that may be substituted, which comprises reacting an optical active 2-aralkyl-3-hydroxypropionic acid having the following general formula (4): 
wherein Ar is an aryl group that may be substituted, with a sulfonic acid halide having the following general formula (5): 
wherein R1 is an alkyl group that may be substituted or an aryl group that may be substituted and X is a halogen atom.
The present invention relates, in a sixth aspect, to a method for producing an optical active 2-aralkyl-3-thiopropionic acid having the following general formula (8): 
wherein Ar is an aryl group that may be substituted and R3 is an alkyl group that may be substituted, an acyl group that may be substituted or an aryl group that may be substituted, which comprises reacting an optical active 2-aralkyl-3-sulfonyloxy-propionic acid having the following general formula (3): 
wherein Ar is an aryl group that may be substituted and R1 is an alkyl group that may be substituted or an aryl group that may be substituted, with a thio-compound having the following general formula (7):
R3xe2x80x94Sxe2x80x94Yxe2x80x83xe2x80x83(7)
wherein R3 is an alkyl group that may be substituted, an acyl group that may be substituted or an aryl group that may be substituted and Y is a hydrogen atom or an alkali metal atom.
In the first invention, as Ar, a phenyl group that may be substituted or a naphthyl group that may be substituted is preferable. A phenyl group that may be substituted with alkyl group, substituted alkyl group, alkoxy group, substituted alkoxy group or halogen atom is more preferable, and phenyl group is the most preferable.
As R1, methyl group is preferable. Especially, Ar being phenyl group and R1 being methyl group is preferable.
From the second to sixth inventions, as Ar, a phenyl group that may be substituted or a naphthyl group that may be substituted is preferable. A phenyl group that may be substituted with alkyl group, substituted alkyl group, alkoxy group, substituted alkoxy group or halogen atom is more preferable, and phenyl group is the most preferable.
As R1, methyl group, ethyl group, n-propyl group, isopropyl group, benzyl group, phenyl group, p-methylphenyl group, p-chlorophenyl group, p-bromophenyl group, p-methoxyphenyl group, o-nitrophenyl group, m-nitrophenyl group, p-nitrophenyl group or 1-naphthyl group is preferable and methyl group is more preferable. Especially, Ar being phenyl group and R1 being methyl group is preferable.
An optical active 2-aralkyl-3-acyloxy-1-propanol which is a starting material of a novel compound of the present invention has the following general formula (6): 
wherein Ar is an aryl group that may be substituted and R2 is a linear or branched alkyl group that may be substituted, a linear or branched alkenyl group that may be substituted or an aryl group that may be substituted.
The compound can be obtained, for example, according to a method described in Tetrahedron Letters vol.31, p1601 (1990). That is, the compound can be obtained by reacting 2-aralkyl-1,3-propanediol, in the presence of a acylating agent, with an enzyme which is able to stereoselectively esterify hydroxyl group of either 1- or 3-position. In another method, the compound can be obtained by reacting 2-aralkyl-1,3-diacyloxypropane with an enzyme that is able to hydrolyze an ester of either 1- or 3-position.
Then, the optical active 2-aralkyl-3-acyloxy-1-propanol expressed by above general formula (6) obtained as described above is reacted with a sulfonic acid halide having the following general formula (5): 
wherein R1 is methyl group, ethyl group, n-propyl group, isopropyl group, benzyl group, p-chlorophenyl group, p-bromophenyl group, p-methoxyphenyl group, o-nitrophenyl group, m-nitrophenyl group, p-nitrophenyl group or 1-naphthyl group, and X is a halogen atom, in the presence of a base, so as to obtain an optical active 2-aralkyl-1-acyloxy-3-sulfonyloxypropane having the following general formula (2): 
wherein Ar is an aryl group that may be substituted, R1 is methyl group, ethyl group, n-propyl group, isopropyl group, benzyl group, p-chlorophenyl group, p-bromophenyl group, p-methoxyphenyl group, o-nitrophenyl group, m-nitrophenyl group, p-nitrophenyl group or 1-naphthyl group and R2 is a linear or branched alkyl group that may be substituted, a linear or branched alkenyl group that may be substituted or an aryl group that may be substituted.
This reaction can be conducted in a non-organic solvent system. However, it is preferable to conduct it in an organic solvent, for example, alcohols such as methanol, ethanol and isopropyl alcohol, halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran and diisopropyl ether, hydrocarbons such as pentane and hexane, acetonitrile, dimethyl sulfoxide, acetone and ethyl acetate. The above solvents can be used alone or in combination of two or more.
As the base, amines such as triethylamine, trimethylamine, diisopropylethylamine, N,N-dimethylaniline and N,N-diethylaniline, aromatic nitrogen compounds such as pyridine, 4-(N,N-dimethylamino)pyridine, imidazole and 2,6-lutidine, or sodium ethoxide, sodium-methoxide, potassium tertiary butoxide, sodium hydride, potassium hydride, calcium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium hydroxide, and potassium hydroxide can be exemplified. These bases can be used alone or in combination of two or more.
The amount of the sulfonic acid halide to be used is preferably 1.0 equivalent or more with respect to a substrate, compound expressed by the general formula (6). If the amount is less than 1.0 equivalent, the efficiency of the reaction is apt to be decreased since all of the raw materials are not reacted. The amount of the base to be used is about equivalent molar with respect to the sulfonic acid halide. The reaction can be conducted in a wide range of temperature, however, usually, a temperature from xe2x88x9210xc2x0 C. to 100xc2x0 C. is preferable. If the temperature is out of this range, the efficiency of the reaction is apt to be lowered. After the reaction has been completed, the aimed product can be obtained easily by adding water to the reaction mixture, followed by extracting with an organic solvent such as toluene and ethyl acetate and removing the solvent. If necessary, the product can be highly purified using silica gel column chromatography and so on.
Then, the thus obtained optical active 2-aralkyl-1-acyloxy-3-sulfonyloxypropane expressed by the general formula (2) is added to an organic solvent and methanol containing a strong base or an aqueous solution containing a strong base, and hydrolyzed so as to an obtain optical active 2-aralkyl-3-sulfonyloxy-1-propanol having the following general formula (1): 
wherein Ar is an aryl group that may be substituted and R1 is methyl group, ethyl group, n-propyl group, isopropyl group, benzyl group, p-chlorophenyl group, p-bromophenyl group, p-methoxyphenyl group, o-nitrophenyl group, m-nitrophenyl group, p-nitrophenyl group or 1-naphthyl group.
As the organic solvent, alcohols such as methanol, ethanol and isopropyl alcohol, halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran and diisopropyl ether, hydrocarbons such as pentane and hexane, acetonitrile, dimethyl sulfoxide, acetone and ethyl acetate are preferable. The above solvents can be used alone or in combination of two or more.
As the strong base, for example, sodium hydroxide and potassium hydroxide are preferable. These bases can be used alone or in combination of two or more. After the reaction has been completed, the aimed product can be obtained easily by extracting with an organic solvent such as toluene and ethyl acetate, followed by removing the solvent. If necessary, the product can be highly purified using silica gel column chromatography and so on.
Then, as described in J. Org. Chem. Vol.52, p25559 (1987), by oxidizing the hydroxyl group of the thus obtained optical active 2-aralkyl-3-sulfonyloxy-1-propanol having the general formula (1) or a known compound of 2-aralkyl-3-sulfonyloxy-1-propanol having the general formula (1) in which Ar is phenyl group and R1 is phenyl group or p-methylphenyl group, or in which Ar is 3-methoxyphenyl group and R1 is p-methylphenyl group, an optical active 2-aralkyl-3-sulfonyloxypropionic acid having the following general formula (3) can be obtained: 
wherein Ar is an aryl group that may be substituted and R1 is an alkyl group that may be substituted or an aryl group that may be substituted.
That is, using one or more of 2,2,6,6-tetramethylpiperidine-1-oxy or 4-substituted 2,2,6,6-tetramethylpiperidine-1-oxy derivative, for example, 4-methoxy-2,2,6,6-tetramethylpiperidine-1-oxy, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxy, 4-benzoyloxy-2,2,6,6-tetramethylpiperidine-1-oxy, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxy and 4-oxo-2,2,6,6-tetramethylpiperidine-1-oxy as a catalyst, in a binary phase system comprised of an organic phase including potassium bromide and a phase transfer catalyst and a water phase, the compound having the general formula (3) can be easily obtained by reacting a compound having the general formula (1) with sodium hypochlorite, followed by extracting, in an acidic condition, with an organic solvent such as toluene and ethyl acetate and removing the solvent. If necessary, the product can be highly purified using silica gel column chromatography and so on.
The optical active 2-aralkyl-3-sulfonyloxypropionic acid having the following general formula (3): 
wherein Ar is an aryl group that may be substituted and R1 is an alkyl group that may be substituted or an aryl group that may be substituted, can be also obtained by the method described below:
Starting material of this method, optical active 2-aralkyl-3-hydroxypropionic acid having the following general formula (4): 
wherein Ar is an aryl group that may be substituted, can be obtained by the method described in Tetrahedron Letters vol.31, p1601 (1990).
That is, by reacting 2-aralkyl-1,3-propanediol, in the presence of an acylating agent, with an enzyme which is able to stereoselectively esterify hydroxyl group of either 1- or 3-position or by reacting 2-aralkyl-1,3-diacyloxypropane with an enzyme which is able to hydrolyze an ester of either 1- or 3-position, an optical active 2-aralkyl-3-acyloxy-1-propanol having the following general formula (6): 
wherein Ar is an aryl group that may be substituted and R2 is a linear or branched alkyl group that may be substituted, a linear or branched alkenyl group that may be substituted or an aryl group that may be substituted, can be prepared, and then by oxidizing the hydroxyl group of the compound having general formula (6) using a suitable method, an optical active 2-aralkyl-3-acyloxypropionic acid having the following general formula (9): 
wherein Ar is an aryl group that may be substituted and R2 is a linear or branched alkyl group that may be substituted, a linear or branched alkenyl group that may be substituted or an aryl group that may be substituted, can be prepared, then, by hydrolyzing the ester having the general formula (9), an optical active 2-aralkyl-3-hydroxypropionic acid having the following general formula (4): 
wherein Ar is an aryl group that may be substituted, can be obtained.
Then, in the presence of a base, the thus obtained optical active 2-aralkyl-3-hydroxypropionic acid having the general formula (4) is reacted with a sulfonic acid halide having the following general formula (5): 
wherein R1 is an alkyl group that may be substituted or an aryl group that may be substituted and X is a halogen atom, so as to obtain an optical active 2-aralkyl-3-sulfonyloxypropionic acid having the following general formula (3): 
wherein Ar is an aryl group that may be substituted and R1 is an alkyl group that may be substituted or an aryl group that may be substituted.
This reaction can be conducted in a non-organic solvent system, however, it is preferable to conduct it in an organic solvent, for example, alcohols such as methanol, ethanol and isopropyl alcohol, halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran and diisopropyl ether, hydrocarbons such as pentane and hexane, acetonitrile, dimethyl sulfoxide, acetone and ethyl acetate. The above solvents can be used alone or in combination of two or more.
As the base, amines such as triethylamine, trimethylamine, diisopropylethylamine, N,N-dimethylaniline and N,N-diethylaniline, aromatic nitrogen compounds such as pyridine, 4-(N,N-dimethylamino)pyridine, imidazole and 2,6-lutidine, or sodium ethoxide, sodium methoxide, potassium tertiary butoxide, sodium hydride, potassium hydride, calcium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate can be exemplified. The above bases can be used alone or in combination of two or more.
The amount of the sulfonic acid halide to be used is preferably 1.0 equivalent or more with respect to a substrate, compound having the general formula (4). If the amount is less than 1.0 equivalent, the efficiency of the reaction is apt to be decreased since all of the raw materials are not be reacted. The amount of the base to be used is about equivalent molar with respect to the sulfonic acid halide. The reaction can be conducted in a wide range of temperature, however, usually, a temperature from xe2x88x9210xc2x0 C. to 100xc2x0 C. is preferable. If the temperature is out of this range, the efficiency of the reaction is apt to be lowered. After the reaction has been completed, the aimed product can be obtained easily by adding water to the reaction mixture, followed by extracting with an organic solvent such as toluene and ethyl acetate and removing the solvent. If necessary, the product can be highly purified using such as silica gel column chromatography and so on.
Next, by reacting the thus obtained optical active 2-aralkyl-3-sulfonyloxypropionic acid with a thio-compound having the following general formula (7):
R3xe2x80x94Sxe2x80x94Yxe2x80x83xe2x80x83(7)
wherein R3 is an alkyl group that may be substituted, an acyl group that may be substituted or an aryl group that may be substituted and Y is a hydrogen atom or an alkali metal atom, an optical active 2-aralkyl-3-thiopropionic acid having the following general formula (8): 
wherein Ar is an aryl group that may be substituted and R3 is an alkyl group that may be substituted, an acyl group that may be substituted or an aryl group that may be substituted, can be obtained.
This reaction can be conducted in a non-organic solvent system, however, it is preferable to conduct it in organic solvent, for example, alcohols such as methanol, ethanol and isopropyl alcohol, halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran and diisopropyl ether, hydrocarbons such as pentane and hexane, acetonitrile, dimethyl sulfoxide, acetone and ethyl acetate. The above solvents can be used alone or in combination of two or more. A base may be added, if necessary.
As the base, amines such as triethylamine, trimethylamine, diisopropylethylamine, N,N-dimethylaniline and N,N-diethylaniline, aromatic nitrogen compounds such as pyridine, 4-(N,N-dimethylamino)pyridine, imidazole and 2,6-lutidine, or sodium ethoxide, sodium methoxide, potassium tertiary butoxide, sodium hydride, potassium hydride, calcium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate can be exemplified. The above bases can be used alone or in combination of two or more.
The reaction can be conducted in a wide range of temperature, however, usually, a temperature from xe2x88x9210xc2x0 C. to 100xc2x0 C. is preferable. If the temperature is out of this-range, the efficiency of the reaction is apt to be lowered. After the reaction has been completed, the aimed product can be obtained easily by extracting with an organic solvent such as toluene and ethyl acetate and removing the solvent. If necessary, the product can be highly purified using silica gel column chromatography and so on.